CA1124234A

CA1124234A - Anthracycline synthesis

Info

Publication number: CA1124234A
Application number: CA329,085A
Authority: CA
Inventors: Jose Alexander; Lester A. Mitscher
Original assignee: University of Kansas Endowment Association (KU Endowment)
Current assignee: University of Kansas Endowment Association (KU Endowment)
Priority date: 1978-06-05
Filing date: 1979-06-05
Publication date: 1982-05-25
Also published as: US4244880A; EP0007403B1; EP0007403A1; JPS55390A; ATE1853T1; EP0043435A1; JPS6254094B2; DE2964088D1

Abstract

ANTHRACYCLINE SYNTHESIS

Abstract of the Disclosure A process for synthesizing the 7-substituted or unsub-stituted 5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene precursors for doxorubicin and related compounds from butadiene and p-benzoquinone and intermedi-ates useful in the synthesis.

Description

The present invention relates generally to a technique for synthesizing doxorubicin and related compounds such as daunomycin, 7-demethoxy daunomycin and carminomycin, and the aglycones thereof. More particularly, the present invention relates to a new and improved process for the production of 7-substituted or unsubstituted 5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacenes which are well known and established intermediates in the synthesis of doxorubicin and related compounds. The present invention also pertains to intermediates useful in the synthesis process.
Doxorubicin is a known anthracycline antibiotic ~e-scribed for example in U.S. Patent No. 3,590,028. Doxo-rubicin, and the closely related compound daunomycin, are antineoplastic agents of established clinical utility.
Doxorubicin hydrochloride, available from Adria Laboratories, Inc., under the trademark Adriamycin~ has been approved by the Food and Drug Administration for use in clinical re-search, and is one of the most powerful anticancer drugs available against numerous forms of cancer.
At present, doxorubicin is produced commercially from a soil fungus by a fermentation process. A suitable fermenta-tion technique for preparing doxorubicin is described in U.S. Patent No. 3,590,028. Such techniques are inherently expensive and limit the types of molecules that can be pro-duced. Because of the inherent disadvantages of presently available commercial techniques for producing doxorubicin and related compounds, substantial effort has been devoted to developing processes for producing such compounds by chemical synthesis.
Techniques for the synthesis of anthracycline antibi-otics such as doxorubicin are known. See, e.g., Wong eL al, ~.Z4234 Canadian Journal of Chemistry, Vol. 51, page 466 (1973); Acton et al, Journal of Medicinal Chemistry, Vol. 17, No. 6, page 659 (1974); Kende et al, Journal of the American Chemical Society, Vol. 97, No. 15, page 4425 (1975) and Vol.
98, No. 7, page 1967 (1976); Sih et al, Tetrahedron Letters, page 3385 (1976);
Swenton et al, Tetrahedron Letters, page 2383 (1977); and Kelly et al, Journal of the American Chemical Society, Vol. 99, page 5513 (1977). None of the known techniques for the total synthesis of anthracycline antibiotics such as doxorubicin have yet been proven to be commercially successful. Because of the demand for, and scarcity of, these compounds, a suitable synthesis technique is highly desired.
The present invention provides a practical technique for synthesizing doxorubicin and related compounds, from readily available and inexpensive starting materials. Specifically, and in accordance with the present invention, doxorubicin and similar compounds may be synthesized from butadiene and p-benzoquinone. In addition, the present invention provides valuable intermediate compounds that are useful in synthesizing doxorubicin and related compounds.
Anthracycline antitumor antibiotics such as doxorubicin, daunomycin, 7-demethoxy daunomycin and carminomycin, including their aglycones, are con-ventionally prepared from known trioxonaphthacene intermediates, in particular, 7R-5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11 trioxonaphthacenes in which R
is H, OH or OCH3, according to well known tec~miques more specifically described below.
In its broadest aspect, the present invention provides a process for producing a 7R-5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene of formula ~L~.24234 O OH
~1 R o OH

wherein R is H, OH or OCH3, which comprises cyclizing and deprotecting with a Friedel-Craft catalyst an aryl ketone of formula O ORl [~ I' OC(C~3)3 wherein R5 is hydrogen, methoxy or acetoxy and Rl and R4 are Cl-C6 alkyl or benzyl groups, to obtain a 2,5,12-trihydroxynaphthacene compound of formula O OH

J

R O OH

and then oxidizing the obtained 2,5,12-trihydroxynaphthacene compound.
For the purposes of this summary, the process will be described as it relates to the production of the trioxonaphthacene where R=OCH3, the precursor for doxorubicin, but it is to be understood the process is equally applicable to the production of the analogous well known intermediates for the - 2a -., 4;~

synthesis of the other anthracyclines.
The trioxonaphthacene is synthesized by first preparing 1,4,4a,5,8,8a-cis-hexahydro-5,8-dioxonaphthalene, a well known reaction product of butadiene and p-benzoquinone and - 2b -~ 2 3 then alkylating it to prepare the 1,4-dihydronaphthalene derivative.
In accordance with the present invention and as more fully described below, the reaction product can be alkylated with a Cl to C6 alkyl or benzylated with a benzyl radical to prepare 5,8-dialkoxy or 5,8-dibenzyloxy-1,4-dihydronaphtha-lene. For the purpose of this discussion, however, it is assumed that the product is methylated to prepare 5,8-dimethoxy-1,4-dihydronaphthalene. This compound is then hydrated to produce 2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, which is in turn alkylated to produce 5,8-dimethoxy-2-t-butoxy-1,2,3,4-tetrahydronaphthalene.
This compound is brominated to provide a synthetically use-ful mixture of 5,8-dimethoxy-6-bromo-2-t-butoxy-1,2,3,4-lS tetrahydronaphthalene and 5,8-dimethoxy-7-bromo-2-t-butoxy-1,2,3 t 4-tetrahydronaphthalene.
This mixture is then converted to i~s lithio analog and reacted with dimethyl-3-methoxyphthalate to produce 5,8-dimethoxy-2-t-butoxy 6- and 7-(3-methoxy-2-carbomethoxy) benzoyl-1,2,3,4-tetrahydronaphthalene. Cyclization with boron trichloride or boron tribromide results in removal of the blocking groups with the formation of 7-methoxy-2,5,12-trihydroxy-1,2,3,4,6,11-hexahydro-6,11-doxonaphthacene.
Oxidation leads to the well known intermediate for the pro-duction of doxorubicin, 7-methoxy-5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene.
The present invention also provides valuable intermedi-a~es useful in the synthesis, including those having the formulas:
A. ~ OR2 t ~J
ORl wherein Rl is a C1-C6 alkyl group or CH2C6H5; R2 is H or C(CH3)3; and R3 is H, Br or Li.

B. O ORl

2~- ~ OC(CH3)3 R5 ORl wherein Rl and R4 are Cl-C6 alkyl groups or CH2C6H5; and R5 is hydrogen, methoxy or acetoxy.
In the synthesis of the present invention, commercially available and inexpensive butadiene and p-benzoquinone are allowed to react under the normal conditions of the Diels-Alder reaction [See O. Diels and K. Alder, Ber., 62, page 2337 (1929)~ to give tbe well-known adduct, 1,4,4a,5,8,8a-cis-hexahydro-5,8-dioxonaphthalene, having the following formula:
~J~ (1) "I
¦I H

Alkylation with a C1-C6 alkyl group or benzylation with a benzyl group under alkaline conditions produces the non-conjugated dihydronaphthalene derivatives of the following formula:
ORl

3 (2) ORl in which Rl represents an alkyl group of from 1 to 6 carbon atoms or the benzyl moiety. The compounds can be defined as 5,8-dialkoxy or 5,8-dibenzyloxy-1,4-dihydronaphthalene.
Hydration of the double bond, as for example under hydroboration-oxidation conditions, produces the tetrahydro-naphthol compound 5,8-dialkoxy or 5,8-dibenzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene of the fol1Owing formula:

3~

OR

\~
OR
in which R1 is the same as defined above.
Etherification to produce the t-butyl ether is accom-plished by acidification in the presence of an appropriate source of t-butyl carbonium ion resulting in the formation of 5,8-dialkoxy or 5,8-dibenzyloxy-2-t-butoxy-1,2,3,4-tetrahydro-naphthalene having the following formula:
~1 OC(CH3)3

(4) \~
ORl in which Rl is the same as defined above.
Bromination produces a mixture of monobromides which may be separated or, in many applications, conveniently used without separation. The bromides have the following formula:
ORl ~ oC(cH3)3 t ¦ ¦ (5) 'I'\' ORl in which Rl is the same as defined above. These compounds may be defined as 5,8-dialkoxy or 5,8-dibenzyloxy-6- and 7-bromo-2-t-butoxy-1,2,3,4-tetrahydronaphthalene.
Lithiation with n-butyl lithium produces the correspond-ing organometallic reagents of the following formula:

, .

~.2~34 ORl -~ OC(CH3)3 t ~ ¦ ~6) \~\/
ORl Reaction of the organometallic reagents with dimethyl-phthalate, dimethyl 3-acetoxyphthalate, or dimethyl 3-methoxyphthalate produces the corresponding aryl ketones of the following formula:

l~ COz~ ~ ~ OC(C~3)3 R5 Rl in which Rl is the same as defined above, R4 is the same as Rl and R5 represents hydrogen, methoxy or acetoxy.
The aryl ketones are cyclized with a Friedel~Crafts catalyst, of which BCL3 or BBr3 are particularly conven-ient, to produce the deblocked naphthacene derivatives of the following formula:
O OH
OH

in which R6 represents H, O~ or OCH3. These compounds may be oxidized, by the method of Lee et al, J. Org. Chem., 41t page 2296 (1976) to the corresponding ketones of the follow-ing formula:
OH
~ (9) in which R6 is the same as defined above.

.
'''~

3~

Su~h ketones are established intermediates in the total synthesis of anthracycline antitumor antibiotics such as daunomycin, 7-demethoxy daunomycin, carminomycin and doxo-rubicin (see A. S. Kende et al, J. Amer. Chem. Soc., 98, page 1967 (1976). More particularly, the ketone intermedi-ate (9) when R6 is H (5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene) leads to 7-demethoxy daunomycin; the ketone intermediate when R6 is OH (5,7,12-trihydroxy-1,2,3,4,6,11-hexahydro-2,6-11-trioxonaphthacene) leads to carminomycin; and the ketone intermediate when R6 is OCH3 (7-methoxy-5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene) leads to daunomycin and doxorubi-cin according to the procedures set forth in this article.
The process of the present invention, previously de-scribed, results in the formation of a number of useful intermediates. Exemplary of the useful intermediates are those having the formula:
OR

ORl in which Rl is Cl-C6 alkyl or benzyl. An example of an intermediate corresponding to the above-identified formula in which Rl is methyl is 5,8-dimethoxy-1,4-dihydronaph-thalene.
Also useful as intermediates are compounds Or the formula:
OR
R3 t~X~ oR2 I

ORl in which Rl is as defined above; R2 is H or C(CH3)3;
and R3 is H, Br or Li.

~.Z~2;~

~ xamples of intermediates corresponding to the above-identified formula include (a) 2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, the compound when Rl is methyl and R2 and R3 are hydrogen; (b) 5,8-dimethoxy-2-S t-butoxy-1,2,3,4-tetrahydronaphthalene, the compound when Rl is methyl, R2 is t-butyl and R3 is hydrogen; (c) 5,8-dimethoxy-6- and 7-bromo-2-t-butoxy-1,2,3,4-tetrahydronaph-thalene, the compound when Rl is methyl, R2 is t-butyl and R3 is bromine; and (d) 5,8-dimethoxy-2-t-butoxy-6- and 7-lithio-1,2,3,4-tetrahydronaphthalene, the compound when R
is methyl, R2 is t-butyl and R3 is lithium.
Other useful intermediates are compounds of the formula:

OC(CH3)3 R5 ORl in which Rl is as defined above; R~ is the same as Rl;
and R5 is hydrogen, methoxy or acetoxy.
Examples of intermediates corresponding to the above-identified formula include 5,8-dimethoxy-2-t-butoxy-6- or 7-(2-methoxycarbonyl) benzoyl-1,2,3,4-tetrahydronaphthalene, the compound when Rl and R4 are methyl and R5 is H; 5,8-dimethoxy-2-t-butoxy-6- or 7-(3-methoxy-2-methoxycarbonyl) benzoyl-1,2,3,4-tetrahydronaphthalene, the compound when Rl and R4 are methyl and R5 is methoxy; and 5,8-dimethoxy-2-t-butoxy-6- and 7-(3-acetoxy-2-methoxycarbonyl) benzoyl-1,2,3,4-tetrahydronaphthalene, the compound when Rl and R4 are methyl and R5 is acetoxy.
The following examples further illustrate preferred em-bodiments of the present invention. The examples should in no way be considered limiting, but are merely illustrative of the various features of the present invention.
Example 1 p-Benæoquinone (10.8 g.) was dissolved in benzene (100 ml.) and cooled in an ice bath. Condensed butadiene (ca.
15 ml.) was added and the mixture was stoppered in a ~.2~
g pressure vessel and then shaken at 50 for 23 hours.
After cooling, the pressure vessel was opened and the benzene was evaporated. The residue weighing 16.6 g. was the pure monoadduct (1,4,4a,5,8,8a-cis-hexahydro-1,4-dioxonaphthalene) corresponding to formula (1) above. Asample crystallized from light petrol melts at 58.
(Reported 58, Diels and Alder, Ber., 62, 2337 (1929).
The product was analyzed and had the following charac-teristics: The nuclear magnetic resonance spectrum (NMR) had the following peaks (CDC13) ~ 1.8-2.9 (4H, allylic H), 3.1-3.4 (2H, m, tertiary H), 5.71 (2H, s, olefinic H), 6.70 (2H, s, olefinic H). The infrared (IR) spectrum has the following peaks (KBr) 3040, 2890, 1655, 1600, 1420, 1255, 1083, 835 cm~l.
Example 2 Alkylation to produce the compound of formula (2) where Rl is methyl, namely 5,8-dimethoxy-1,4-dihydronaph-thalene was accomplished as follows:
The Diels-Alder adduct of Example 1 (38 g.) dissolved in acetone (200 ml.) was refluxed with dimethyl sulfate (65 g.) and potassium carbonate (80 g.) for 18 hours. The potassium salts were filtered off and washed with acetone.
The combined filtrate and washings on evaportation gave a thick liquid (43 g.) which solidified on standing. It was crystallized from light petrol. The first crop was 19.45 g.
Another 17.2 g. more was obtained from the mother liquor on subsequent crystallizations. m.p. 50.
The compound has the following characteristics: NMR
(CDC13), ~3.25 (4H, s, allylic H), 3.76 (6H, s, OCH3), 30 5.83 (2H, s, olefinic H), and 6.60 (2H, s, aromatic H). IR
(nujol) 1610, 1485, 1463, 1252, 1096, 1081 cm 1.
Example 3 The 5,8-dimethoxy-2-hydroxy-1,2,3,4~tetrahydronaph-thalene compound of formula (3) may be prepared as follows:
The olefin of Example 2 (7 g.) was dissolved in THF
(30 ml.) in a flask fitted with an addition funnel and reflux condenser and stoppered with rubber septa. It was purged with dry nitrogen and an atmosphere of nitrogen was 3~

maintained throughout the experiment. The solution was cooled in ice and a lM solution of diborane in THF (37 ml., 1 mole equiv.) was added dropwise during 1/2 hour. It was then kept stirred at room temperature for 2 hours. 5 ml.
of water was added with cooling to decompose the excess hydride.
After introducing 25 ml. of a 3M solution of sodium hydroxide, 13 ml. of 30 H2O2 was added dropwise at such a rate that the temperature of the reaction mixture did not rise above 50. It was then heated at 50 (bath) for 1-1/2 hours and left stirring at room temperature overnight.
The aqueous layer was saturated with KCl and the organic layer was separated. The aqueous layer was extracted with ether once.
The combined organic extract was dried over K2CO3 and evaporated. The residue weighing 6.55 g. was the pure hydroxy compound. Crystallization from benzene-light petrol furnished 5.7 g. of the pure secondary alcohol. m.p.
130-131.5.
The product had the following characteristics: NMR
(CDC13) ~ 1.6-2.1 (3H, multiplet, C3H and OH), 2.2-3.~
(4H, benzylic ~, multiplet), 3.56 (6H, s, OCH3), 3.8-4.3 (lH, multiplet CH-OH) and 6.60 (2H, s, aromatic H). IR
(nujol) 3360-3280, 1610, 1480, 1462, 1376, 1255, 1093, 1075, 1035, 780, 708 cm~1.
Example 4 The t-butyl ether of 5,8-dimethoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene, a compound of formula (4), was pre-pared as follows:
The alcobol of Example 3 (30 9.) suspended in methylene chloride (100 ml.) was cooled in dry ice-alcohol bath to -20. Boron trifluoride-etherate (3.0 ml.) and 100%
H3PO4 (1.5 ml.) were added to it. Condensed isobutylene (100 ml.) was added to the mixture and shaken at room tem-perature for 16 hours. All the suspended solid had disap-peared during this time. The reaction mixture was washed three times with water and then dried over sodium sulfate.
The residue on evaporation was diluted with light petrol 3~

(125 ml.)and Eiltered through a small bed of alumina to remove a trace of unreacted starting material. The filtrate on evaporation furnished the pure t-butyl ether, 5,8-dimethoxy 2-t-butoxy-1,2,3,4-tetrahydronaphthalene, as a colorless thick syrup (35.2 g.) (92.6~ yield).
The ether had the following characteristics: NMR
(CDC13) ~ 1.21 (9H, s, t-butyl), 1.4-3.3 (6H, multiplet, alicyclic H), 3.75 (6H, s, OCH3), and 6.62 (2H, s, aromatic H). IR (film) 2290, 2822, 1603, 1480, 1438, 1390, 0 1358, 1250, 1190, 1100, 1040, 982, 903 cm 1.
Example 5

5,8-Dimethoxy-6- and 7-bromo-2-t-butoxy-1,2,3,4-tetra-hydronaphthalene compounds of formula (5), were prepared as follows:
To the t-butyl ether of Example 4 (35.1 g.) dissolved in chloroform (150 ml.), acetamide (8 g.) was added and stirred to dissolve. The solution was then cooled in ice.
A solution of bromine (21.7 g.) in chloroform (30 ml.) was added to the ice cold solution of the t-butyl ether with stirring during 2 hours. It was kept stirred at 0 for an additional 0.5 hr. after the addition of bromine. The chloroform solution was then washed with water (2x), sodium bisulfite (2x) and water (2x). It was dried over sodium sulfate and evaporated. The residue was a pale yellow liquid.
It was dissolved in light petrol (200 ml.) and filtered through alumina (Merck) 60 9. The filtrate and light petrol washings were evaporated to furnish the pure monobromo com-pounds. A~ter vacuum drying at 40/0.3 mm. for 1 hour, the compounds weighed 42.7 g., (33.7% yield).
The monobromo compounds had the following characteris-tics: NMR (CDC13) ~ 1.23 (9H, s, t-butyl), 1.6-3.3 (6H, multiplet, alicylcic H), 3.76 (6H, s, OCH3) and 6.77 (lH, s, aromatic H). MS m/e 342, 344 (M+), 288, 286 (~+-iso-butylene), 268, 270 (M+-tBuOH), 207 ([M -Br +
isobutylene]), etc.

~.2'~34 Example 6 5,8-Dimethoxy-2-t-butoxy-6- or 7-(Z-methoxycarbonyl) benzoyl-1,2,3,4-tetrahydronaphthalene compounds of formula (7) where R5 is hydrogen, were prepared as follows:
The nuclear bromo derivative of the t-butyl ether of Example 5 (34.3 g.) was dissolved in 500 ml. of freshly dis-tilled (from benzophenone ketyl) tetrahydrofuran in a 3-necked flask fitted with a thermometer and dropping funnel.
The solution was cooled to -95 to -100 in a diethyl ether-liquid nitrogen bath. The n-butyl lithium in THF (68 ml. of 1.5 M solution, 1.1 equivalents) was added to the stirred solution maintaining the temperature at -95 to -90. It was then allowed to warm up to -80 during 45 min. A solution of dimethyl phthalate (23 g., 1.2 equiv.) in dry THF (25 ml.) was then added during 1/2 hour. When the addition was complete, the temperature of the reaction mixture was -40. It was then left stirring at room tem-perature overnight. Acetic acid (10 ml.) was added and the THF was evaporated. The residue was taken in ether and washed with water, aqueous sodium bicarbonate (2x) and water 2x). The ether extract was dried over sodium sulfate and evaporated. The residue weighing 51.05 g. was a thick yellow liquid. It contained, in addition to the condensa-tion product, small amounts of dimethyl phthalate and the starting t-butyl ether.
This sample (25 g.) on high performance liquid chroma-tography on a Sigel column using ethyl acetate-chloroform (1:9) as eluent furnished 16.3 g. of the pure compound as a mixture of isomers. This set to a resinous solid on stand-ing (yield 65.2%). However, it is not necessary to purifythe condensation product for the next (cyclization) step.
The cyclization product is highly insoluble and can be puri-fied easily by solvent washing.
The product of this example has the following charac-teristics: NMR (CDC13) ~ 1.20 (9H, s, t-butyl), 1.5-3.2 (4H, multiplet), 3.26 (3H, s, CO2CH3), 3.65 and 3.73 (3H each, singlets, OCH3), 6.95 (lH, s, aromatic) and 7.3~
(4~, quartet, J=4Hz, aromatic). IR 1730, 161Q, 1595, 1460, ~.2~23~L

1402, 1270, 1220 cm 1. Ma~s spectrum (MS) m/e 426 (M ), 425 (M -1), 379, 369, (M -57), 332 and 162 ~base peak ~ +

Example 7 2,5,12-Trihydroxy-1,2,3,4,6,11-hexahydro-6,11-dioxo-naphthacene, a compound of formula (8) where R6 is H was then prepared as follows:
The ortho-keto ester of Example 6 (0.5 g.) was dis-solved in methylene chloride (50 ml.) and cooled in ice.
Boron trichloride gas was passed into the solution until there was an excess. It was stirred at room temperature until TLC showed that there was no more starting material and all the compound was converted to the tetracyclic com-pound ( 48 hour~). When the reaction was complete, the methylene chloride and excess BC13 were evaporated off in vacuum.
~he residue was triturated with 0.5 N hydrochloric acid (30 ml.) and filtered. The red solid was the practically pure hydroxy compound l0.35 g.) 96.4% yield.
The dioxonaphthacene compound had the following charac-teristics: NMR (CF3CO2H) ~ 2.0-3.3 (6H, multiplet), 5.75 (lH, multiplet), 7.92 (2H, multiplet, aromatic) and 8.4 (2H, multiplet, aromatic). IR (KBr) 3420, 1618, 1580, 1395, 1245 cm~l. Ultraviolet (UV) (EtOH) ~ max (~)~ 513 (4802), 482 (6985), 456 (6086), 326 (2439), 2a7 (6369), 256 (27995), 252 (28508) nm. MS m/e 310 (M+), 292 (M+-18), 291 (M -18-1), 290.
ExamPle 8 A second method for the preparation of 2,5,12-trihydroxy-1,2,3,4,6,11-hexahydro-6,11-dicxonaphthacene is as follows:
The keto ester of Example 6 (1.3 9 ) dissolved in -14- ~ 3~

dichloromethane (30 ml.) was cooled to -70. A lM solution of B~r3 in methylene chloride (20 ml.) was added dropwise.
The reaction mixture was then allowed to warm up to -15.
The slow appearance of the cyclic alcohol as well as the bromo compound could be detected on TLC (developed with ethyl acetate-chloro~orm (2:8)). After allowing it to stand in the refrigerator (ca.-10) for 16 hours, the reaction mixture was decomposed by adding water. The multiphase mix-ture was filtered and the solid washed with water. The filtrate was separated into the two layers. The organic layer was washed with water and evaporated to give 0.8 g. of the desired alcohol. This was purified by dissolving the residue in methylene chloride and crystallizing the desired alcohol by adding light petrol~
Example 9 5,8-Dimethoxy-2-t-butoxy-6- and 7-(3-methoxy-2-carbo-methoxy) benzoyl-1,2,3,4-tetrahydronaphthalene, a compound of formula (7) where R5 is OC~3 was prepared as follows:
To the lithio derivative of the t-butyl ether prepared as in Example 6 (from ~ g. of bromo compound) was added a solution of dimethyl 3-methoxyphthalate (4.9 g.) in dry THF
(15 ml.) dropwise over 0.5 hr. The reaction was stirred a~
room temperature overnight, acetic acid (2 ml.) was added and the THF was evaporated. The residue was worked up as in Example 6 to give 10.2 g. of oily product which was used in the next example without further purification.
ExamPle 10 7-Methoxy-2,5,12-trihydroxy-1,2,3,4,6,11-hexahydro-

6,11-dioxonaphthacene, a compound of formula (8) where R6 is OCH3 was prepared as follows:
The aryl ketone of Example 9 (5.0 g.) was dissolved in 250 ml. of methylene chloride and cooled in ice. Boron tri-chloride gas was passed into the solution until there was an excess. The reaction mixture was stirred at room tempera-ture ~or two days and the volatiles were removed under re-duced pressure. The residue was triturated with 0.5 N
hydrochloric acid and fi~tered. The red solid was puri~ied by preparative scale hplc chromatography using silica gel 15 ~ ~ ~Z~ 3'~

and methylene chloride/methanol as solvent followed by crystallization from methylene chloride. The product had the following characteristics: IR peaks at 3420, 1620, 1580 cm 1. MS m/e 340 (M ), 322 (M -18~, 321 and 320.
Example 11 2,5,7,12-Tetrahydroxy-1,2,3,4,6,11-hexahydro-6,11-dioxonaphthacene, a compound of formula (8~ where R6 is OH
can be prepared according to the procedures of Examples 9 and 10, but using dimethyl 3-acetoxyphthalate in place of dimethyl 3-methoxyphthalate.
Example 12 When a sample of the alcohol o~ Example 10 (20 mg.) was oxidized according to the procedure of Lee et al, J. Org.
Chem., 41, page 2302, and the product crystallized from pyridine, the product had m.p. 249-250 and was identical in chromatographic and spectroscopic properties to 7-methoxy-5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphtha-cene as described by A. S. Kende et al., J. Am. Chem. Soc., 98, page 1968 (1976)o This known intermediate can then be used to produce daunomycin or doxorubicin according to the procedure set forth in this article.
Similarly, the compound of Example 7 can be oxidized to produce 5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxo-naphthacene, a known precursor for 7-demethoxy daunomycin and the compound of Example 11 oxidized to produce 5,7,12-trihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene, a known precursor for carminomycin.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a 7R-5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene of formula wherein R is H, OH or OCH3, which comprises cyclizing and deprotecting with a Friedel-Craft catalyst an aryl ketone of formula wherein R5 is hydrogen, methoxy or acetoxy and R1 and R4 are C1-C6 alkyl or benzyl groups, to obtain a 2,5,12-trihydroxynaphthacene compound of formula and then oxidizing the obtained 2,5,12-trihydroxynaphthacene compound.

2. A process according to claim 1 wherein the aryl ketone is obtained by reacting a lithium compound of formula wherein the lithium atom occupies the 6- or 7-position and Rl is as defined above, with an ester of phthalic acid of formula wherein R4 and R5 are as defined above.

3. A process according to claim 2 wherein the lithium compound is ob-tained by lithiating a bromine compound of formula wherein Rl is as defined above and wherein the bromine atom occupies the 6- or 7-position.

4. A process according to claim 3 wherein the bromine compound is obtained by brominating an ether of formula wherein Rl is as defined above.

5. A process according to claim 4 wherein the ether is obtained by reacting a 2-hydroxy compound of formula with a tert-butyl carbonium ion-containing compound.

6. A process according to claim 5 wherein the 2-hydroxy compound is ob-tained by hydrating a 1,4-dihydronaphthalene compound of formula wherein Rl is as defined above.

7. A process according to claim 6 wherein the 1,4-dihydronaphthalene compound is obtained by reacting 1,4,4a,5,8,8a-cis-hexahydro-5,8-dioxonaphtha-lene of formula with an alkylating agent containing Cl-C6 alkyl groups or with a benzylating agent.

8. A process according to claim 7 wherein the 1,4,4a,5,8,8a-cis-hexa-hydro-5,8-dioxonaphthalene is obtained by reacting p-benzoquinone with butadiene.

9. A process for producing 5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene comprising:
(a) reacting p-benzoquinone with butadiene to produce 1,4,4a,5,8,8a-cis-hexahydro-5,8-dioxonaphthalene;
(b) alkylating with a Cl-C6 alkyl group or benzylating with a benzyl group the reaction product of (a) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-1,4-dihydronaphthalene;
(c) hydrating the compound of (b) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene;
(d) etherification of the compound of (c) in the presence of t-butyl carbonium ion to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-2-t-butoxy-1,2,3,4-tetrahydronaphthalene;
(e) brominating the ether of (d) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-6- and 7-bromo-2-t-butoxy-1,2,3,4-tetrahydronaphthalene;
(f) lithiating the compound of (e) followed by acylation of the lithio derivative with dimethyl phthalate to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-2-t-butoxy-6- or 7-(2-methoxycarbonyl)benzoyl-1,2,3,4-tetrahydro-naphthalene;
(g) cyclization and deprotection of the compound of (f) with a Friedel-Crafts catalyst to produce 2,5,12-trihydroxy-1,2,3,4,6,11-hexahydro-6,11-dioxonaphthacene; and (h) oxidation of the compound of (g) to produce 5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene.

10. A process for producing 7-methoxy-5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene comprising:
(a) reacting p-benzoquinone with butadiene to produce 1,4,4a,5,8,8a-cis-hexahydro-5,8-dioxonaphthalene;
(b) alkylating with a C1-C6 alkyl group or benzylating with a benzyl group the reaction product of (a) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-1,4-dihydronaphthalene;
(c) hydrating the compound of (b) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene;
(d) etherification of the compound of (c) in the presence of a t-butyl carbonium ion to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-2-t-butoxy-1,2,3,4-tetrahydronaphthalene;
(e) brominating the ether of (d) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-6- and 7-bromo-2-t-butoxy-1,2,3,4-tetrahydronaphthalene;
(f) lithiating the compound of (e) followed by acylation of the lithio derivative with dimethyl 3-methoxyphthalate to produce 5,8-dialkoxy or 5,8-dibenzyloxy-2-t-butoxy-6- or 7-(3-methoxy-2-methoxycarbonyl)benzoyl-1,2,3,4-tetrahydronaphthalene;
(g) cyclization and deprotection of the compound of (f) with a Friedel-Crafts catalyst to produce 7-methoxy-2,5,12-trihydroxy-1,2,3,4,6,11-hexahydro-6,11-dioxonaphthacene; and (h) oxidation of the compound of (g) to produce 7-methoxy-5,12-dihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene.

11. A process for producing 5,7,12-trihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene comprising:
(a) reacting p-benzoquinone with butadiene to produce 1,4,4a,5,8,8a-cis-hexahydro-5,8-dioxonaphthalene;
(b) alkylating with a Cl-C6 alkyl group or benzylating with a benzyl group the reaction product of (a) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-1,4-dihydronaphthalene;
(c) hydrating the compound of (b) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene;
(d) etherification of the compound of (c) in the presence of a t-butyl carbonium ion to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-2-t-butoxy-1,2,3,4-tetrahydronaphthalene;
(e) brominating the ether of (d) to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-6- and 7-bromo-2-t-butoxy-1,2,3,4-tetrahydronaphthalene;
(f) lithiating the compound of (e) followed by acylation of the lithio derivative with dimethyl 3-acetoxyphthalate to produce 5,8-dialkoxy- or 5,8-dibenzyloxy-2-t-butoxy-6- or 7-(3-acetoxy-2-methoxycarbonyl)benzoyl-1,2,3,4-tetrahydronaphthalene;
(g) cyclization and deprotection of the compound of (f) with a Friedel-Crafts catalyst to produce 2,5,7,12-tetrahydroxy-1,2,3,4,6,11-hexahydro-6,11-dioxonaphthacene; and (h) oxidation of the compound of (g) to produce 5,7,12-trihydroxy-1,2,3,4,6,11-hexahydro-2,6,11-trioxonaphthacene.